Use of s-10-hydroxy-10,11-dihydro-carbamazepine for the treatment of anxiety and bipolar disorders

ABSTRACT

The present invention relates to the use of a racemate of the compound of formula (1) consisting of at least 85% S-enantiomer and not more than 15% R-enantiomer or of pharmaceutically acceptable salts of said racemate or of the S-enantiomer of formula I or of pharmaceutically acceptable salts of said enantiomer for the treatment of anxiety or other psychiatric disorders with underlying anxiety symptomatologies or for the treatment of affective and attention disorders; pharmaceutical compositions for that purpose and packages comprising said pharmaceutical compositions together with instructions for the use of said compositions for the treatment of anxiety or other psychiatric disorders with underlying anxiety symptomatologies or of affective and attention disorders.

The present invention relates to new pharmaceutical uses of acarbamazepine derivative.

More particularly the present invention relates to new pharmaceuticaluses for a racemate of the carbamazepine derivative of formula I

and its pharmaceutically acceptable salts.

Racemic licarbazepine (MHD, formula I,10-hydroxy-10,11-dihydro-carbamazepine), the main metabolite of theantiepileptic drug oxcarbazepine (Trileptal®), is well known from theliterature [see for example Schuetz H. et al., Xenobiotica (GB), 16(8),769-778 (1986)] and can be prepared synthetically starting fromoxcarbazepine according to conventional methods. It was demonstratedthat the racemate (formula I) and both of its pure enantiomers are ofequal efficacy against epilepsy.

In accordance with the present invention, it was now surprisingly foundthat the S-enantiomer of the compound of formula I is substantially moreefficacious than the R-enantiomer in the prevention and the treatment ofaffective and attention disorders, anxiety and other psychiatricdisorders with underlying anxiety symptomatologies.

Hence, the present invention pertains to the use of the racemate of thecompound of formula I consisting of at least 85% S-enantiomer and notmore than 15% R-enantiomer, hereafter referred to as “the racemate”, theuse of the pure S-enantiomer, and to the use of pharmaceuticallyacceptable salts of said racemate or enantiomer, for the treatment ofaffective and attention disorders, anxiety and other psychiatricdisorders with underlying anxiety symptomatologies.

One embodiment of the present invention pertains to the use of theS-enantiomer of the compound of formula I or of a pharmaceuticallyacceptable salt thereof for the treatment of affective and attentiondisorders, anxiety and other psychiatric disorders with underlyinganxiety symptomatologies.

The term “affective and attention disorders” as used herein includes,but is not restricted to depression or other psychiatric disorders likeuni- and bi-polar disorders, e.g. manic-depressive psychoses, extremepsychotic states, e.g. mania, pre-menstrual dysphoric disorder,post-partum depression, post-menopausal depression,neurodegeneration-related depressive symptoms and depression.

The term “anxiety or other psychiatric disorders with underlying anxietysymptomatologies” as used herein includes, but is not restricted togeneral anxiety disorders, social anxiety disorders, post traumaticstress disorder, obsessive compulsive disorder, panic and anxietyoccurring following cessation of psychostimulant intake.

The suitability of the agents of the invention for the treatment ofaffective and attention disorders can be evidenced, for example, intests suitable for detecting drugs reversing psycho-motor stimulatoryeffects. In particular, it can be evidenced in the Vogel conflict testdescribed in the Example below. The person skilled in the pertinent artis fully enabled to select further relevant test models to prove suchactivity. The usefulness of the agents of the invention in the treatmentof the above-mentioned disorders can be confirmed in suitable clinicalstudies. Suitable clinical studies are in particular randomized,double-blind, placebo-controlled, parallel studies in bi-polar mooddisorders patients or patients having psychiatric disorders withunderlying anxiety symptomatologies.

The Vogel conflict test described in the Examples below is the standardtest to detect psychiatric, mainly anxiolytic and antidepressant drugaction since various classes of anxiolytic and antidepressant drugs areeffective in this test and since there is a high co-morbidity betweenanxiety states and other psychiatric, e.g., depression disorders. Thevery surprising specific and high efficacy of, above all, theS-enantiomer in this test is therefore indicative of drug activity inanxiety, depression and other psychiatric disorders as defined above.

The obtained results from the Vogel conflict test clearly demonstratethat the R-enantiomer at the highest dose used (200 mg/kg) is lessefficacious than the S-enantiomer at the lowest dose used (50 mg/kg),whereas the potency/efficacy ratio of the racemate is between that ofthe R- and S-enantiomers. This finding is very surprising in the lightof the anticonvulsant findings where all 3 compounds are equipotent,i.e., their potency is within a factor of less than 2.

For the treatment of the diseases mentioned above, appropriate dosagewill of course vary depending upon, for example, the ratio of thedifferent enantiomers, the host, the disease to be treated, the mode ofadministration and the nature and severity of the condition beingtreated. However, in general, satisfactory results in animals areindicated to be obtained at a daily dosage of from about 1 to 300 mg/kganimal body weight of the racemate or the S-enantiomer. In largermammals, for example humans, an indicated daily dosage of the racemateor the S-enantiomer is in the range from about 10 to about 3000 mg of acompound according to the invention, conveniently administered, forexample, in divided doses up to four times a day.

The racemate or the enantiomer may be administered in any usual manner,e.g. orally, for example in the form of tablets or capsules, orparenterally, for example in the form of injection solutions orsuspensions.

The present invention also provides pharmaceutical compositionscomprising the racemate of the compound of formula I or pharmaceuticallyacceptable salts of said racemate consisting of at least 51%S-enantiomer and not more than 49% R-enantiomer, preferably at least 85%S-enantiomer and not more than 15% R-enantiomer, or the S-enantiomer, inassociation with at least one pharmaceutical carrier or diluent, inparticular, for the use in the treatment of affective and attentiondisorders or anxiety or other psychiatric disorders. with underlyinganxiety symptomatologies. Such compositions may be manufactured in aconventional manner.

Unit dosage forms may contain for example from about 2.5 mg to about1000 mg of the racemate or the S-enantiomer.

The invention further relates to the use of a racemate or theS-enantiomer of the compound of formula I or of pharmaceuticallyacceptable salts of said racemate or enantiomer for the manufacture of apharmaceutical composition for the treatment of affective and attentiondisorders or anxiety or other psychiatric disorders with underlyinganxiety symptomatologies.

The invention further provides a method for the treatment of affectiveand attention disorders in a subject in need of such treatment, whichcomprises administering to said subject a therapeutically effectiveamount of a racemate according to the invention or of the S-enantiomeror of a pharmaceutically acceptable salt of said racemate or enantiomer.

The invention further provides a method for the treatment of anxiety orother psychiatric disorders with underlying anxiety symptomatologies ina subject in need of such treatment, which comprises administering tosaid subject a therapeutically effective amount of a racemate accordingto the invention or of the S-enantiomer or of a pharmaceuticallyacceptable salt of said racemate or enantiomer.

One preferred embodiment of the invention relates to the use of theracemate of the invention or the S-enantiomer in the treatment ofbipolar mood disorders.

Furthermore, the present invention provides a package comprising apharmaceutical composition comprising the racemate of the compound offormula I consisting of at least 51% S-enantiomer and not more than 49%R-enantiomer, preferably at least 85% S-enantiomer and not more than 15%R-enantiomer, or the S-enantiomer, or a pharmaceutically acceptablesalts of said racemate or enantiomer, in association with at least onepharmaceutical carrier or diluent together with instructions for the useof said pharmaceutical composition in the treatment of affective andattention disorders or anxiety or other psychiatric disorders withunderlying anxiety symptomatologies.

Preferably, the racemate consists of at least 95% S-enantiomer and notmore than 5% R-enantiomer, more preferably of at least 98% S-enantiomerand not more than 2% R-enantiomer, most preferably of at least 99.5%S-enantiomer and not more than 0.5% R-enantiomer

The racemates of the invention can, e.g., be obtained by mixing the pureenantiomers of the compound of formula I. The pure enantiomers of thecompound of formula I can be obtained starting from the racemate byprocedures known as such. The racemate may be separated into itsenantiomers through the formation of diastereomeric salts, for exampleby salt formation with an enantiomer-pure chiral acid, or by means ofchromatography, for example by HPLC, using chromatographic substrateswith chiral ligands.

In one embodiment of the invention, the pure enantiomers of the compoundof formula I are prepared according to the procedures described in theExamples below.

The following Examples serve to illustrate the invention withoutlimiting the invention in its scope.

Abbreviations Ac acetyl aqu. Aqueous dansyl5-(dimethylamino)-1-naphthalenesulfonyl Et ethyl HPLC high pressureliquid chromatography Me methyl NMR nuclear magnetic resonance RT roomtemperature THF tetrahydrofuran Ts tosyl

EXAMPLES Example 1 Procedure for the Enantioselective TransferHydrogenation of 10-Oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylicacid amide toR(−)-10,11-Dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide

To a mixture of 10-oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylicacid amide (300 mg, 1.189 mmol) andRuCl[(1R,2R)-p-TsNCH(C₆H₅)CH(C₆H₅)NH₂](η⁶-p-cymene, Aldrich,Switzerland) (8.8 mg, 0.0138 mmol) in CH₂Cl₂ (15 ml) is added dropwise apremixed solution of formic acid and NEt₃ (5:2, 328 mg:289 mg) at 23° C.and stirred for 10 min. The clear solution is heated to reflux for 16 h.The reaction mixture is cooled to RT, diluted with CH₂Cl₂ (20 ml) andneutralised with aqu. NaHCO₃. After washing with brine the solution isconcentrated under reduced pressure. The residue is purified by flashchromatography on silica gel using a 6:1 EtOAc-MeOH mixture as eluent toafford ofR(−)-10,11-dihydro-10-hydroxy-5H-dibenzo[b,f]azepine-5-carboxamide(enantiomeric purity (ee)>99% determined by HPLC on Chiracel OD,Retention time: 9.46 min. [α]_(D) ^(rt)=−195.3° (ethanol). ¹H-NMR (400MHz, CDCl₃):7.70-7.20 (m, 8 H), 5.30 (br s,1 H), 5.10-4.60 (br s, 2 H),3.75-3.40 (m, 1 H), 3.20-2.90 (m, 1 H), 2.50 (br s, 2 H). NMR-Datasrefer to Lit.: Benes, J et al., J. Med. Chem. 1999, 42, 2582-2587.Molecular weight: 254.291

Example 2 Procedure for the Enantioselective Transfer Hydrogenation of10-Oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylic acid amide toS(+)-10,11-Dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide

To a mixture of 10-oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylicacid amide (300 mg, 1.189 mmol) andRuCl[(1S,2S)-p-TsNCH(C₆H₅)CH(C₆H₅)NH₂(η⁶-p-cymene) (11 mg, 0.0173 mmol)in CH₂Cl₂ (15 ml) is added in two portions a premixed solution of formicacid and NEt₃ (5:2, 656 mg:578 mg) at 23° C. and stirred for 10 min.After that formic acid is added (50 μl) and the clear solution is heatedto reflux for 16 h. The reaction mixture is cooled to RT, diluted withCH₂Cl₂ (20 ml) and neutralised with aqu. NaHCO₃. After washing withbrine the solution is concentrated under reduced pressure. The residueis purified by flash chromatography on silica gel using a 6:1 EtOAc-MeOHmixture as eluent to afford ofS(+)-10,11-dihydro-10-hydroxy-5H-dibenzo[b,f]azepine-5-carboxamide(ee>99% by HPLC on Chiracel OD). Retention time: 12.00 min. [α]_(D)^(rt)=+196.6° (ethanol). ¹H-NMR (400 MHz, CDCl₃):7.70-7.20 (m, 8 H),5.30 (br s,1 H), 5.10-4.60 (br s, 2 H), 3.75-3.40 (m, 1 H), 3.20-2.90(m, 1 H), 2.50 (br s, 2 H). NMR-Datas refer to Lit.: Benes, J et al., J.Med. Chem. 1999, 42, 2582-2587. Molecular weight: 254.291

Alternative production: To a mixture of10-oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylic acid amide (300mg, 1.189 mmol) andRuCl[(1S,2S)-p-dansyl-NCH(C₆H₅)CH(C₆H₅)NH₂](η⁶-p-cymene) (8.5 mg, 0.012mmol) in CH₂Cl₂ (15 ml) is dropwise a premixed solution of formic acidand NEt₃ (5:2, 328 mg:289 mg) at 23° C. and stirred for 10 min. Theclear solution is heated to reflux for 16 h. The reaction mixture iscooled to RT, diluted with CH₂Cl₂ (20 ml) and neutralised with aqu.NaHCO₃. After washing with brine the solution is concentrated underreduced pressure. The residue is purified by flash chromatography onsilica gel using a 6:1 EtOAc-MeOH mixture as eluent to afford ofS(+)-10,11-dihydro-10-hydroxy-5H-dibenzo[b,f]azepine-5-carboxamide.

Example 3 Preparation ofRuCl[(1S,2S)-p-dansylNCH(C₆H₅)CH(C₆H₅)NH₂](η⁶-p-cymene)

a) Preparation of (S,S)-5-dimethylamino-naphthalene-1-sulfonic acid(2-amino-1,2-diphenyl-ethyl)-amide: To a solution of(S,S)-diphenylethylenediamine (250 mg, 1.2 mmol) and triethylamine (0.5ml) in THF is added dropwise a solution of dansyl chloride (318 mg, 1.2mmol) in THF (2 ml) at 0° C. After stirring 16 h at RT the solvent isremoved in vacuum and the residue is resolved in methylenchloride (20ml). The organic solution is washed with NaHCO₃ solution (5 ml), driedover Na₂SO₄ and after filtration the solvent is removed. Flashchromatographie afford (S,S)-5-dimethylamino-naphthalene-1-sulfonic acid(2-amino-1,2-diphenyl-ethyl)-amide as yellow oil which crystallizes bydrying in vacuum. M: 445.59. ¹H-NMR (400 MHz, CDCl₃):8.36 (t, J=7.5 Hz,2 H), 8.17 (dd, J=7.2, 1.2 Hz, 1 H), 7.47 (dd, J=8.8 Hz, 1 H), 7.34 (dd,J=8.5 Hz, 1 H), 7.24-7.16 (m, 4 H), 7.11 (d, J=7.5 Hz, 1 H), 6.99-6.74(m, 6 H), 4.61 (d, J=8.5 Hz, 1 H), 4.20 (d, J=8.5 Hz, 1 H), 2.80 (s, 6H).

b) Preparation ofRuCl[(1S,2S)-p-dansylNCH(C₆H₅)CH(C₆H₅)NH₂(η⁶-p-cymene): A solution of(S,S)-5-dimethylamino-naphthalene-1-sulfonic acid(2-amino-1,2-diphenyl-ethyl)-amide (80 mg, 0.18 mmol), NEt₃ (36 mg, 0.36mmol) and [RuCl₂(p-cymene)]₂ (55 mg, 0.09 mmol) in 2-propanol is heatedat 80° C. for 1 h. The solvent is removed after that und the dark redresidue is washed with water (2 ml). The solid is dried in vacuum andused without any purification. M: 715.34.

Example 4 Vogel Conflict Test

a) Description of method: The method, which detects anxiolytic andrelated other psychiatric activity, follows that described by Vogel etal, Psychopharmacologia 1971; 21:1-7 Anxiolytics and antidepressants(e.g., Fontana et al., Psychopharmacology 1989; 98(2):157-62) of variousclasses increase punished drinking.

Rats are deprived of water for 48 hours and are then placed individuallyinto a transparent Plexiglas enclosure (15×32×34 cm) with a floorconsisting of stainless steel bars (0.4 cm) spaced 1 cm apart The backwall of the enclosure is made of opaque Plexiglass thereby concealingthe observer from the experimental animal. In the centre of the oppositewall, 5 cm above the floor, a metal water spout protrudes into the cageand is connected to one pole of a shock generator (Apelex: Type 011346).The other pole of the shock generator is connected to the metal gridfloor. The rat is left to explore until it found the water spout. Then,every time it drinks, it receives a slight electric shock (1.7 mA, 1sec.) 2 seconds after it starts lapping. The number of shocks received(punished drinkings) is counted during a 3 minute period. 15 rats arestudied per group. The test is performed blind. Compounds are evaluatedat 50, 100 and 200 mg/kg, administered p.o. 60 minutes before the test,and compared with a vehicle control group. Clobazam (64 mg/kg),administered under the same experimental conditions, is used asreference substance. All substances are evaluated within the sameexperiment and compared with the same vehicle and reference substancecontrols. Data are analyzed by comparing treated groups with vehiclecontrol using unpaired Student's t tests.

b) Results: The results are summarized in Tables 1-3. They clearlydemonstrate that the R-enantiomer at the highest dose used (200 mg/kg)is less efficacious than the S-enantiomer at the lowest dose used (50mg/kg), whereas the potency/efficacy ratio of the Racemate is betweenthat of the R- and S-enantiomers. In addition, whereas the maximumefficacy of the R-enantiomer is less than that of the positive control,i.e., clobazam, the efficacy of the S-enantiomer surpasses that ofclobazam at all doses tested.

TABLE 1 EFFECTS OF THE RACEMATE AND CLOBAZAM IN THE VOGEL CONFLICT TESTIN THE RAT (15 RATS PER GROUP) M3 PUNISHED DRINKING (number of shocks)(mg/kg) p % change p.o. −60 min mean ± s.e.m. value from control Vehicle 4.4 ± 0.2 — — 50  5.9 ± 0.5 * 0.012 +34% 100  8.4 ± 1.0 *** 0.001 +91%200 10.4 ± 1.5 *** 0.001 +136%  CLOBAZAM  8.2 ± 1.1 ** 0.003 +86% 64mg/kg p.o. −60 min Student's t test: * = p < 0.05; ** = p < 0.01; *** =p < 0.001

TABLE 2 EFFECTS OF THE R-ENANTIOMER AND CLOBAZAM IN THE VOGEL CONFLICTTEST IN THE RAT (15 RATS PER GROUP) M4 PUNISHED DRINKING (number ofshocks) (mg/kg) p % change p.o. −60 min mean ± s.e.m. value from controlVehicle 4.4 ± 0.2 — — 50 5.0 ± 0.4 NS 0.203 +14% 100 5.5 ± 0.5 NS 0.088+25% 200 7.4 ± 1.3 * 0.033 +68% CLOBAZAM 8.2 ± 1.1 ** 0.003 +86% 64mg/kg p.o. −60 min Student's t test: NS = Not Significant; * = p < 0.05;** = p < 0.01

TABLE 3 EFFECTS OF THE S-ENANTIOMER AND CLOBAZAM IN THE VOGEL CONFLICTTEST IN THE RAT (15 RATS PER GROUP) M5 PUNISHED DRINKING (number ofshocks) (mg/kg) p % change p.o. −60 min mean ± s.e.m. value from controlVehicle  4.4 ± 0.2 — — 50  8.4 ± 1.3 ** 0.006 +91% 100  9.5 ± 1.0 ***0.000 +116%  200 10.5 ± 1.3 *** 0.000 +139%  CLOBAZAM  8.2 ± 1.1 **0.003 +86% 64 mg/kg p.o. −60 min Student's t test: ** = p < 0.01; *** =p < 0.001

1. A method for the treatment of general anxiety disorders, socialanxiety disorders, post traumatic stress disorder, obsessive compulsivedisorder or panic and anxiety occurring following cessation ofpsychostimulant intake in a subject in need of such treatment, whichcomprises administering to said subject a therapeutically effectiveamount of a racemate of the compound of formula I,

wherein said racemate consists of at least 85% S-enantiomer and not morethan 15% R-enantiomer, or pharmaceutically acceptable salts thereof. 2.The method of claim 1 wherein the racemate consists of at least 95%S-enantiomer and not more than 5% R-enantiomer.
 3. The method of claim 1wherein the racemate consists of at least 98% S-enantiomer and not morethan 2% R-enantiomer.
 4. A method for the treatment of affective andattention disorders in a subject in need of such treatment, whichcomprises administering to said subject a therapeutically effectiveamount of a racemate of the compound of formula I

wherein said racemate consists of at least 85% S-enantiomer and not morethan 15% R-enantiomer, or pharmaceutically acceptable salts thereof. 5.The method of claim 4 wherein the affective and attention disorders arebipolar disorders.
 6. The method of claim 4 wherein the racemateconsists of at least 95% S-enantiomer and not more than 5% R-enantiomer.7. The method of claim 4 wherein the racemate consists of at least 98%S-enantiomer and not more than 2% R-enantiomer.